The Bet Inhibitor Bay 1238097 Shows Efficacy In Braf Wild-Type And Mutant Melanoma Models

BET proteins recognize histone acetylation marks and play an essential role in transcription elongation. BRD4, the best studied family member, binds to the regulatory regions of oncogenes such as MYC, thereby controlling its expression and that of the downstream transcriptome. Following the identification of the first selective inhibitors, BET proteins have been shown to play essential roles in hematological and, more recently, in solid tumors. Here we studied the efficacy of the novel BET inhibitor BAY 1238097 in melanoma models. BAY 1238097 was a potent BET inhibitor with IC50 values of 47 and 295 nM for BRD4 BD1 and BD2, respectively. In NanoBRET assays, the interaction between BRD4, BRD3 or BRD2 with histone H4 was blocked in intact cells with IC50 values of 65 nM, 294 nM and 642 nM, respectively. In addition to its strong anti-proliferative activity in several hematological tumor models, BAY 1238097 was also effective in several melanoma cell lines with GI50 values below 500 nM in BRAF wild-type (CHL-1, COLO-792, B16F10, IPC-298, MeWo) as well as BRAF mutant (A375, G-361, SK-MEL-30, LOX-IMVI, SK-MEL-5, MEL-HO) models. Resistant cell lines with GI50 values above 10 μM were identified in both the BRAF wild-type and mutant groups. ChIP analysis performed in BRAF wild-type CHL-1 cells showed that BAY 1238097 displaced BRD4 from regulatory regions of oncogenes such as MYC, leading to loss of expression. The oxygen consumption rates of the melanoma cell lines were measured and we found that cell lines sensitive to BAY 1238097 depended on oxidative phosphorylation rather than glycolysis for energy production. In vivo efficacy was determined for BAY 1238097 in three patient-derived melanoma models harboring the wild-type BRAF gene. Daily, oral treatment with 7.5 mg/kg BAY 1238097 led to significantly reduced tumor growth (39% T/C) in one model. Interestingly, this model was resistant to dacarbazine given i.p. at 100 mg/kg daily. No biologically significant anti-tumor activity was observed for the two other models treated with the same conditions (62% and 70% T/C, respectively). Altogether the results show BAY 1238097 to be a potent inhibitor of BRD4 binding to histones. The compound has strong anti-proliferative activity in different melanoma models, regardless of the BRAF mutation status but related to the metabolic activity. One out of three patient-derived melanoma models with wild-type BRAF responded to BAY 1238097 treatment in vivo. Future studies will help to better characterize the impact of BET inhibition on melanoma. Citation Format: Bernard Haendler, Kathy A. Gelato, Laura Schockel, Tatsuo Sugawara, Pascale Lejeune, Heidrun Ellinger-Ziegelbauer, Amaury E. Fernandez-Montalvan, Simon Holton, Stephan Siegel, Melanie Heroult, Annette Walter, Stuart Ince, Matthias Ocker. The BET inhibitor BAY 1238097 shows efficacy in BRAF wild-type and mutant melanoma models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4703.